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Meeting Report: Innovations in Prostate Cancer Research Wadih Arap,1,2 Martin Trepel,3 Bruce R Published OnlineFirst February 1, 2008; DOI: 10.1158/0008-5472.CAN-07-3232 Meeting Report Meeting Report: Innovations in Prostate Cancer Research Wadih Arap,1,2 Martin Trepel,3 Bruce R. Zetter,4 and Renata Pasqualini1,2 Departments of 1Genitourinary Medical Oncology and 2Cancer Biology, The University of Texas M.D.Anderson Cancer Center, Houston, Texas; 3University of Freiburg Medical Center, Department of Hematology and Oncology and Institute for Molecular Medicine and Cell Research, Freiburg, Germany; and 4Children’s Hospital, Harvard Medical School, Boston, Massachusetts Introduction cells.In closing, he proposed that, because compounds may inter- The incidence of prostate cancer has increased with serum fere in different steps during angiogenesis, combination antiangio- prostate-specific antigen (PSA) screening.Although organ-confined genic therapy should be evaluated as a therapeutic approach. prostate cancer can be cured by surgery and/or radiation therapy, metastatic disease cannot.Androgen ablation in this setting has Detection and Prediction long been recognized as effective, but tumors almost invariably Otis Brawley (Winship Cancer Center) analyzed population-based relapse over time; unfortunately, outcome of patients with meta- PSA screening for prostate cancer detection; he questioned such static androgen-independent disease remains poor despite incre- programs regarding cost/labor intensity (3).Dr.Brawley emphasized mental improvements in chemotherapy.The purpose of this that three kinds of prostate cancer must be distinguished: tumors that ‘‘Special AACR Conference in Prostate Cancer’’ was (a) to provide do not require treatment (proven to exist), tumors that require a specialized forum for presentation of state-of-the-art disease- treatment but cannot be treated effectively and result in patient death specific research; (b) to attract innovative investigators from other (also proven to exist), and tumors that require treatment and can be fields; and (c) to introduce new cutting-edge technologies into sufficiently treated (may exist but uncertainty remains).Distinction prostate cancer basic, translational, and clinical investigation. among such phenotypes is mandatory to offer management options (3). Marsha Moses (Children’s Hospital of Boston) delivered a mole- Opening Keynotes cular account of the regulation of angiogenesis from an angiogenic Throughout the conference, the theme of androgen independence switch through tumor progression and the resulting clinical impli- in prostate cancer was addressed.Howard Scher (Memorial Sloan- cations.Identifying mechanisms that cause such tumor angiogenic Kettering Cancer Center) focused on androgen-regulated gene switch might lead to novel diagnostic and therapeutic approaches. expression and approaches to inhibiting the androgen receptor (1). Dr.Moses proposed that, because proteolysis is among the earliest Gene profiling revealed that androgen receptor expression persisted processes involved in the angiogenic switch, a critical step to be in all stages of hormonal treatment.Dr.Scher stated that many genes addressed is the degradation of the endothelial basement membrane involved in androgen receptor signaling were found differentially and adjacent extracellular matrix proteins with the release of expressed in androgen-dependent versus androgen-independent angiogenic factors (4).Thus, the study of matrix metalloproteases, prostate cancer; some may be therapeutic targets in androgen- cysteine and serine proteases, ADAM and ADAMTS families might independent disease.Because DNA acetylation regulates androgen yield mechanistic insights into the processing of growth factors and receptor expression, histone deacetylase inhibitors (such as vorino- their receptors, and the influence on the equilibrium between stat and LBH589) can influence prostate cancer cells.Indeed, such angiogenic factors and their endogenous inhibitors. compounds down-regulate androgen receptor expression and inhibit A strategy to integrate microanatomic features and molecular prostate cancer cell growth.Clinical trials (LBH589 alone or in com- biomarkers to predict prostate cancer progression was introduced bination with docetaxel; vorinostat plus antiandrogens) are ongoing. by Carlos Cordo´n-Cardo (Columbia University).Dr.Cordo ´n-Cardo Judah Folkman (Children’s Hospital of Boston) galvanized the presented a model that uses a combination of clinical data, histo- audience while broadly discussing angiogenesis as an organizing pathology, quantitative assessment of concentration and localization in situ principle in medicine and biology (2).Based on the hypothesis that of relevant proteins, transcriptional analysis, and computer- the growth of normal and neoplastic tissues is angiogenesis assisted data analysis.Such data can be used for a systems biology dependent, Dr.Folkman illustrated that blood vessel formation is approach (5) to generate personalized outcome prediction of the not only closely related to development, wound healing, and cancer response to different therapies against prostate cancer. but also to certain nonmalignant eye and joint diseases.This Nanotechnology applications are being rapidly developed for paradigm has now been clinically validated with the Food and Drug tumor imaging, predictive oncology, and targeted therapy.Jonathan Administration approval of bevacizumab.The advantage of the Simons (Prostate Cancer Foundation) presented an overview about angiogenic endothelial cell as a therapeutic target was discussed in the promise of nanotechnology as tool in translational prostate terms of accessibility and genetic stability compared with tumor cancer research (6).Dr.Simons showed that encapsulating luminescent quantum dots with amphiphilic block copolymers and linking the polymer to tumor-targeting ligands generated Note: W.Arap and M.Trepel contributed equally to this work. multifunctional nanoparticles with evident potential for detection of This AACR-sponsored Special Conference, co-organized by Renata Pasqualini and molecular targets in vivo. Bruce R.Zetter, was held December 6 to 9, 2006, in San Francisco, California.The key speakers and affiliations are provided as supplemental information. Requests for reprints: Renata Pasqualini or Wadih Arap, The University of Texas M.D.Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Tumor Microenvironment Phone: 713-792-3873; Fax: 713-745-2999; E-mail: [email protected] or warap@ The vascular and peripheral nervous systems share a unique mdanderson.org. I2008 American Association for Cancer Research. feature: Both are branched networks requiring guidance to ensure doi:10.1158/0008-5472.CAN-07-3232 their proper positioning.Anne Eichmann (Institut National de la Sante www.aacrjournals.org 635 Cancer Res 2008; 68: (3). February 1, 2008 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2008 American Association for Cancer Research. Published OnlineFirst February 1, 2008; DOI: 10.1158/0008-5472.CAN-07-3232 Cancer Research et de la Recherche Medicale) discussed her findings on the role of tional alterations that drive prostate cancer progression for the axon guidance molecules in angiogenesis (7).Dr.Eichmann showed development of biomarkers and therapeutic targets.Dr.Collins that specialized endothelial cells (resembling axonal growth cones in profiled whole genome copy number changes in genomes of neurons) locate at the tips of outgrowing capillaries to guide growing hormone-naive lymph node metastases from matched primary capillaries along vascular endothelial growth factor gradients. tumors with comparative genomic hybridization.Matched primary Juri Gelovani (M.D. Anderson Cancer Center) presented new tumors and lymph node metastases showed very similar profiles but techniques of noninvasive molecular imaging for in vivo detection distinct from tumors that did not metastasize (14). and monitoring of therapy in preclinical models.Dr.Gelovani 18 described [ F]FEAU positron emission tomography (PET) for Tumor Progression and Metastasis imaging of Herpes simplex virus type-1 thymidine kinase expression in vivo (8).PET was also used with epidermal growth factor Warren Heston (Cleveland Clinic) originally cloned the gene receptor (EGFR) kinase-specific radiolabeled tracers to image the encoding prostate-specific membrane antigen (PSMA).Dr.Heston heterogeneity of EGFR expression and signaling activity. discussed PSMA as a target in prostate cancer.PSMA expression The unfolded protein response allows cells to adapt to adverse increases in normal-to-neoplastic prostate epithelium transforma- conditions affecting the endoplasmic reticulum.Amy Lee (Univer- tion; it is expressed in a fraction of prostate cancers; and it is sity of Southern California/Norris Cancer Center) reported stress also a vascular target in other solid tumors.PSMA functions as an induction of glucose-regulated protein (GRP)-78 in tumor micro- internalizing target; thus, radionuclide-conjugated PSMA anti- environment.GRP-78 is overexpressed in many tumors (9) and bodies resulted in antitumor responses and displayed enhanced Dr.Lee detailed its role in prostate cancer progression and drug sensitivity for bone metastasis detection.Antitumor effects were resistance through blockage of Bax and caspase-7 activation. observed in preclinical models with an auristatin-linked toxin GRP-78 overexpression is associated with a poor prognosis and PSMA antibody as a vascular target (15). resistance to therapy. Of any given primary tumor, only a minority
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